The nature of drugs

There’s a certain linear, not to say reductionist, thinking that goes on about disease. Arnold Mandrell, a researcher studying schizophrenia, stated in the 1987 science best seller Chaos that we have a conceptual problem in our approach to psychiatric drug treatment, a conceptual problem that applies pretty much to the thinking about most disease processes. He stated that we seem to believe that, “The underlying paradigm remains: one gene one peptide one enzyme one neurotransmitter one receptor one animal behavior one clinical syndrome one drug.” Characterizing and treating illness might not be this simple.

That’s not to say that single chemical–single receptor drug interactions don’t exist. A number of drugs we have today are a testament to this model. But as science and medical research get into ever more sophisticated drug definitions, we’ll have to come to terms with the simplicity of our current conceptual models. From the simple exchange of oxygen and carbon dioxide in breathing to the sophistication of the Krebs cycle, every living system is a unique assemblage of checks and balances. At a simple level, how else to explain why certain drugs work in some patients and not in others? At a more sophisticated level, how else to explain why AIDS responds to a treatment consisting of a cocktail of antiviral drugs while the response to each individual drug declines?

Nature’s Medicine: Plants That Heal, a book recently published by the National Geographic Society, describes many medical treatments, some thousands of years old, based on roots, herbs, teas, and even certain kinds of tree bark. As the author, Joel Swerdlow, points out, it is not likely that positive effects from these materials are due to single chemical species acting on single proteins or enzymes. More likely there are hundreds, if not thousands, of chemicals extracted or created from these plants, and they probably affect many systems in the body.

Ultimately, for drug treatment to be successful, it will have to take into consideration all the systems of the body and their cyclical interactions. To evaluate new drug candidates, our tools will have to improve. In this issue of Modern Drug Discovery, we explore some of the possibilities. Senior Editor Mark Lesney writes about using cells themselves as the next step in drug efficacy assays, that is, evaluating a drug in something more resembling “field” conditions. Other articles show that even though we’ve become better at using today’s robotic tools to screen new chemical candidates for indications of drug efficacy, few new drugs have come to market as a result.

Teraflops of data now exist that are derived from the linear model embodied in today’s high-throughput screening evaluations, but we still can’t model living systems well enough to predict both drug efficacy and system toxicity. New screening tools, cell assays, and the success of projects from groups like the proteome consortium will undoubtedly provide a new set of tools that will provide us the means to solve these problems.